The Fas/Fas‐ligand system: a mechanism for immune evasion in human breast carcinomas

Abstract

Breast tumors are frequently associated with a predominantly lymphocytic infiltrate, which constitutes an immune response against the tumor. In spite of this massive infiltrate, the immune response appears to be inefficient and the tumor is able to evade it. We propose that in breast cancer, tumor escape from immunological surveillance results from the induction of apoptosis of Fas-bearing activated lymphocytes by FasL-bearing breast cancer cells. To test this proposal we studied the expression of FasL by human breast carcinomas and the MCF-7 breast cancer cell line by RT-PCR, immunohistochemistry, and Western Blot. Moreover, we describe the presence of apoptosis and Fas expression in the lymphocytic population surrounding the tumor. Strong membranous and cytoplasmic staining was detected in ductal carcinomas and hyperplastic breast tissue, but it was absent from normal breast tissue. No staining was found in normal glands in the non-tumor quadrants; however, the normal appearing ducts surrounding the carcinoma (tumor quadrant) showed intense immunoreactivity. Apoptosis was found predominantly among the lymphocytic population, as well as in the blood vessels and fibro-fatty tissue close to the tumor. Further characterization of apoptotic cells demonstrated that they were CD3+ cells. Our results suggest the breast tumors may elude immunological surveillance by inducing, via the Fas/FasL system, the apoptosis of activated lymphocytes. Recent data have demonstrated FasL RNA in other tumor types. Upregulation of FasL expression in hyperplastic and normal breast ducts close to the tumor also suggests a possible role in early neoplastic transformation and proliferation.

Transcription factor EGR3 is involved in the estrogen-signaling pathway in breast cancer cells

“…The luciferase reporter assay suggested that fasL is another target gene for EGR3 in breast cancer. There are several reports concerning the expression of Fas ligands in tumors derived from several organs such as the breast (Gutierrez et al 1999) and ovary (Rabinowich et al 1998). FasL expression in these malignant cells is considered to be one of the mechanisms involved in escape from immune surveillance, leading encountered T cells into apoptosis, and it would bring about an advantage in the progress and metastasis of the tumor cells in vivo.…”

Macrophages, estrogen and the microenvironment of breast cancer

“…Although their function within the tumor is not clear, up to 80% of the leukocytes in some breast carcinomas are macrophages [26,27]. Tissue macrophages are recruited from peripheral monocytes, which are known to express estrogen receptors (ER) [19].…”

“…To establish that these cells were indeed macrophages, sections were stained with a monoclonal antibody recognizing CD68, a macrophage-specific antigen. Immunoreactive cells were localized to the leukocytes around and within the tumor; thus, positive staining for CD68 identified the cells expressing ARO as macrophages.Although their function within the tumor is not clear, up to 80% of the leukocytes in some breast carcinomas are macrophages [26,27]. Tissue macrophages are recruited from peripheral monocytes, which are known to express estrogen receptors (ER) [19].…”

Expression of B7‐H1 in breast cancer patients is strongly associated with high proliferative Ki‐67‐expressing tumor cells

“…2,3 However, the presence of an existing immune tolerance in patients with advanced cancer may limit the clinical effectiveness of such therapeutic strategies. 4 Several mechanisms have been attributed to the immune defect seen in breast cancer patients with advanced disease; where a lower number of blood lymphocytes, 5 elevated T regulatory lymphocytes, 6 defective dendritic cells 7 and expression of FasL in breast cancer 8 were described.…”